The present invention relates to novel oxazolidines which find utility as intermediates in the preparation of C-13 acyloxy sidechain-bearing taxanes such as paclitaxel and analogs thereof. The present invention also relates to novel methods of preparing the oxazolidines, as well as to novel methods of coupling the oxazolidines to form the aforementioned sidechain-bearing taxanes.
Taxanes are diterpene compounds finding utility in the pharmaceutical field. For example, paclitaxel (Taxol(copyright)), a taxane having the structure: 
where Ph is phenyl, Ac is acetyl and Bz is benzoyl, has been found to be an effective anticancer agent. The compound taxotere, having the following structure, has also been reported for anticancer use: 
Naturally occurring taxanes such as paclitaxel may be found in plant materials, and have been isolated therefrom. Such taxanes may, however, be present in plant materials in relatively small amounts so that, in the case of paclitaxel, for example, large numbers of the slow-growing yew trees forming a source for the compound may be required. The art has thus continued to search for synthetic, including semi-synthetic routes for the preparation of naturally occurring taxanes such as paclitaxel, as well as routes for the preparation of pharmaceutically useful analogs thereof. In particular, efficient. methods for the addition of a C-13 acyloxy sidechain to a taxane core are sought as the presence of the C-13 acyloxy sidechain imparts pharmacological activity or provides a taxane more readily converted to one having such pharmacological activity.
The present invention provides novel oxazolidine compounds useful as intermediates for the preparation of C-13 acyloxy sidechain-bearing taxanes. Novel methods for coupling the oxazolidine intermediates of the invention with taxanes containing a hydroxyl group directly bonded at C-13 to provide the aforementioned C-13 acyloxy sidechain-bearing taxanes are also provided, as are methods of preparing the novel oxazolidines of the present invention.
In particular, novel oxazolidines of the formulae I and II are provided: 
where
R1 is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl;
R1* is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl, with the proviso that R1* is not tert-butoxycarbonyl when R2 is aryl;
R2 is aryl, heterocyclo or alkyl;
R4 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, or heterocyclo;
R5 and R6 are (a) each independently alkyl; or (b) together with the carbon atom to which they are bonded, form a cycloalkyl, cycloalkenyl or heterocyclo group; and
R8 is alkyl or aryl;
and salts thereof.
The novel oxazolidines of the present invention are useful as intermediates in the preparation of C-13 acyloxy sidechain-bearing taxanes such as paclitaxel and analogs thereof. Thus, the present invention further provides novel methods for coupling the intermediates of the formulae I and II with a taxane containing a hydroxyl group directly bonded at C-13 to provide C-13 acyloxy sidechain-bearing taxanes of the following formula VI: 
where R1 is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl; R2 is aryl, heterocyclo or alkyl; and T is a taxane moiety directly bonded at C-13 of said moiety. Coupling may be achieved by the methods described following.
In one embodiment of the invention, a compound of the formula VI or salt thereof may be prepared by a method comprising the steps of:
(a) contacting a compound of the following formula III or salt thereof: 
xe2x80x83with a compound of the following formula IV:
HOxe2x80x94Txe2x80x83xe2x80x83(IV),
xe2x80x83in the presence of a coupling agent, to form a compound of the following formula V or salt thereof: 
xe2x80x83where R1, R2, R5, R6 and T are as defined above; and
(b) contacting said compound of the formula V or salt thereof with a ring-opening agent to form said compound of the formula VI or salt thereof. Each of the steps (a) (when R1 is R1*) and (b) of this method are themselves novel methods. Additionally, the compounds of the formulae III and V and salts thereof are novel when R1 is R1*.
Compounds of the formula III include compounds of the formula I where R4 is hydrogen. A compound of the formula I where R4 is other than hydrogen may be converted to a compound of the formula III where R1 is R1* by a novel method comprising the step of hydrolyzing said compound of the formula I where R4 is other than hydrogen to form said compound of the formula III. Any compound capable of effecting the hydrolysis may be employed as the hydrolyzing agent. Exemplary hydrolyzing agents include aqueous bases such as aqueous hydroxides (e.g., metal hydroxides such as barium hydroxide, or preferably, alkali metal hydroxides such as lithium, sodium or potassium hydroxide). Contact with a base provides a carboxylic acid salt of a compound of the formula III. Further contact with an acid, preferably a mineral acid such as HCl, provides a compound of the formula III where R4 is hydrogen, that is, which contains a free carboxylic acid group. Compounds of the formula III where R1 is other than R1* may be prepared by methods analogous to those methods described herein for the preparation of compounds of the formula III where R1 is R1*.
In another embodiment of the invention, a compound of the formula VI or salt thereof may be prepared by a method comprising the steps of:
(a) contacting a compound of the following formula VII or salt thereof: 
xe2x80x83with a compound of the following formula IV:
HOxe2x80x94Txe2x80x83xe2x80x83(IV),
xe2x80x83in the presence of a coupling agent, to form a compound of the following formula VIII or salt thereof: 
xe2x80x83where R1, R2, R8 and T are as defined above; and
(b) contacting said compound of the formula VIII or salt thereof with a ring-opening agent to form said compound of the formula VI or salt thereof. Each of the steps (a) and (b) of this method are themselves novel methods. Additionally, the compounds of the formulae VII and VIII and salts thereof are novel.
Compounds of the formula VII are compounds of the formula II where R4 is hydrogen. A compound of the formula II where R4 is other than hydrogen may be converted to a compound of the formula VII by a novel method comprising the step of hydrolyzing said compound of the formula II where R4 is other than hydrogen to form said compound of the formula VII. Hydrolysis of a compound of the formula II to form a compound of the formula VII may be conducted as described above for the hydrolysis of a compound of the formula I where R4 is other than hydrogen to form a compound of the formula III.
The ring of the present oxazolidine compounds is numbered herein as follows: 
With respect to the 4- and 5-position carbon atoms, the oxazolidine compounds of the formulae I and II may exist as the four stereoisomers Ia or iIa, Ib or IIb, Ic or IIc and Id or IId, respectively, as follows: 
As the stereochemistry of taxanes may affect their pharmaceutical activity, it is desirable to employ oxazolidine intermediates which will provide the final taxane product with the stereochemistry sought. While the use of stereoisomeric mixtures of a compound of the formula I or II is contemplated herein, the use of a single stereoisomer providing the desired stereochemistry in the final product may achieve a more efficient use of the starting materials and less complicated separation and purification procedures.
The present invention is described further as follows.
The terms xe2x80x9calkylxe2x80x9d or xe2x80x9calkxe2x80x9d, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 12 carbons in the normal chain. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents may include one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (xe2x80x94COOH), alkyloxycarbonyl, alkylcarbonyloxy, carbamoyl (NH2xe2x80x94COxe2x80x94), amino (xe2x80x94NH2), mono- or dialkylamino, or thiol (xe2x80x94SH).
The terms xe2x80x9clower alkxe2x80x9d or xe2x80x9clower alkylxe2x80x9d, as used herein, denote such optionally substituted groups as described above for alkyl having 1 to 6 carbon atoms in the normal chain.
The terms xe2x80x9calkoxyxe2x80x9d or xe2x80x9calkylthioxe2x80x9d, as used herein, denote an alkyl group as described above bonded through an oxygen linkage (xe2x80x94Oxe2x80x94) or a sulfur linkage (xe2x80x94Sxe2x80x94), respectively. The term xe2x80x9calkyloxycarbonylxe2x80x9d, as used herein, denotes an alkoxy group bonded through a carbonyl group. The term xe2x80x9calkylcarbonylxe2x80x9d, as used herein, denotes an alkyl group bonded through a carbonyl group. The term xe2x80x9calkylcarbonyloxyxe2x80x9d, as used herein, denotes an alkylcarbonyl group which is bonded through an oxygen linkage. The terms xe2x80x9cmonoalkylaminoxe2x80x9d or xe2x80x9cdialkylaminoxe2x80x9d denote an amino group substituted by one or two alkyl groups as described above, respectively.
The term xe2x80x9calkenylxe2x80x9d, as used herein alone or as part of another group, denotes such optionally substituted groups as described for alkyl, further containing at least one carbon to carbon double bond. Exemplary substituents include one or more alkyl groups as described above, and/or one or more groups described above as alkyl substituents.
The term xe2x80x9calkynylxe2x80x9d, as used herein alone or as part of another group, denotes such optionally substituted groups as described for alkyl, further containing at least one carbon to carbon triple bond. Exemplary substituents include one or more alkyl groups as described above, and/or one or more groups described above as alkyl substituents.
The term xe2x80x9ccycloalkylxe2x80x9d, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic hydrocarbon ring systems, preferably containing 1 to 3 rings and 3 to 7 carbons per ring. Exemplary unsubstituted such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, and adamantyl. Exemplary substituents include one or more alkyl groups as described above, and/or one or more groups described above as alkyl substituents.
The term xe2x80x9ccycloalkenylxe2x80x9d, as used herein alone or as part of another group, denotes such optionally substituted groups as described above for cycloalkyl, further containing at least one carbon to carbon double bond forming a partially unsaturated ring. Exemplary substituents include one or more alkyl groups as described above, and/or one or more groups described above as alkyl substituents.
The terms xe2x80x9carxe2x80x9d or xe2x80x9carylxe2x80x9d, as used herein alone or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplary unsubstituted such groups include phenyl, biphenyl, and naphthyl. Exemplary substituents include one or more, preferably three or fewer, nitro groups, alkyl groups as described above, and/or groups described above as alkyl substituents.
The term xe2x80x9carylcarbonylxe2x80x9d, as used herein alone or as part of another group, denotes an aryl group as described above bonded through a carbonyl group.
The terms xe2x80x9cheterocycloxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d, as used herein alone or as part of another group, denote optionally substituted, fully saturated or unsaturated, aromatic or non-aromatic cyclic groups having at least one heteroatom in at least one ring, preferably monocyclic or bicyclic groups having 5 or 6 atoms in each ring. The heterocyclo group may, for example, have 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring. Each heterocyclo group may be bonded through any carbon or heteroatom of the ring system. Exemplary heterocyclo groups include the following: thienyl, furyl, pyrrolyl, pyridyl, imidazolyl, pyrrolidinyl, piperidinyl, azepinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, benzofurazanyl, and especially, tetrahydropyranyl (e.g. 4-tetrahydropyranyl). Exemplary substituents include one or more alkyl groups as described above, and/or one or more groups described above as alkyl substituents.
The terms xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d, as used herein alone or as part of another group, denote chlorine, bromine, fluorine, and iodine.
The term xe2x80x9ctaxane moietyxe2x80x9d, as used herein, denotes moieties containing the core structure: 
which core structure may be substituted and which may contain ethylenic unsaturation in the ring system thereof. Such moieties having an oxetane ring fused at the 4- and 5-positions, and an ethylenic double bond between C-11 and C-12, such as are found in paclitaxel, are preferred.
The term xe2x80x9ctaxanexe2x80x9d, as used herein, denotes compounds containing a taxane moiety as described above. The term xe2x80x9cC-13 acyloxy sidechain-bearing taxanexe2x80x9d, as used herein, denotes compounds containing a taxane moiety as described above, further containing an acyloxy sidechain directly bonded to said moiety at C-13 through the oxygen of the oxy group of the acyloxy substituent.
The term xe2x80x9chydroxy (or hydroxyl) protecting groupxe2x80x9d, as used herein, denotes any group capable of protecting a free hydroxyl group which, subsequent to the reaction for which it is employed, may be removed without destroying the remainder of the molecule. Such groups, and the synthesis thereof, may be found in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d by T. W. Greene, John Wiley and Sons, 1981, or Fieser and Fieser. Exemplary hydroxyl protecting groups include methoxymethyl, 1-ethoxyethyl, 1-methoxy-1-methylethyl, benzyloxymethyl, (xcex2-trimethylsilylethoxy)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl, and 2,2,2-trichloroethoxymethyl.
The term xe2x80x9csaltxe2x80x9d, as used herein, includes salts with organic and/or inorganic acids and/or bases.
The term xe2x80x9cacylxe2x80x9d, as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxyl group from the group xe2x80x94COOH of an organic carboxylic acid. The term xe2x80x9cacyloxyxe2x80x9d, as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (xe2x80x94Oxe2x80x94).
Preparation of oxazolidines of the Formulae I and II
The oxazolidines of the formulae I and II and salts thereof may be prepared starting with a compound of the following formula i: 
where R1 is hydrogen, arylcarbonyl, alkoxycarbonyl or alkylcarbonyl; R2 is aryl, heterocyclo or alkyl; R4 is hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl or heterocyclo; and where R3 is hydrogen or the group R3P, where R3P is the group: 
where R5 and R6 are as defined above, and R7 is alkyl or aryl. Compounds of the formula i may be prepared as described in, or by methods analogous to those described in, U.S. application Ser. No. 07/975,453, filed Nov. 12, 1992, or U.S. application Ser. No. 08/263,869, filed Jun. 21, 1994, or as described below.
Compounds of the formula I and salts thereof may be prepared from compounds of the formula i and salts thereof where R1 is R1* by a novel method comprising the step of contacting said compound of the formula i or salt thereof with an acid catalyst, and additionally, where R3 in said compound of the formula i or salt thereof is hydrogen, with a compound of the formula ii or iii described following. The aforementioned compounds of the formulae ii and iii have the following structures: 
where R5, R6 and R7 are as defined above, and where R5a (i) is a group such that R5axe2x80x94CH2xe2x80x94 is R5 or (ii) forms, together with R6 and the atoms to which R5a and R6 are bonded, a cycloalkenyl or heterocyclo group containing at least one carbon to carbon double bond. Compounds of the formulae ii and iii are commercially available or may readily be prepared by known methods. Exemplary compounds of the formula ii include the compounds: 
or, most preferably, 2-methoxypropene. Exemplary compounds of the formula iii include the compounds: dimethoxypropane, 
Novel compounds of the following formula iv and salts thereof: 
where R1*, R2, R3P and R4 are as defined above may be formed as intermediates in the aforementioned method when a compound of the formula i or salt thereof in which R3 is hydrogen is contacted with the compound of the formula ii or iii. In the presence of acid catalyst, the compound iv or salt thereof undergoes conversion to a compound of the formula I or salt thereof.
Compounds of the formula II and salts thereof may be prepared from compounds of the formula i and salts thereof by a novel method comprising the step of contacting a compound of the formula i or salt thereof where R3 is hydrogen, in the presence of an acid catalyst, with a compound of the following formula vi:
HC(OR8)3xe2x80x83xe2x80x83(vi)
where R8 is as defined above. Compounds of the formula vi are commercially available or may readily be prepared by known methods. Exemplary compounds of the formula vi include trimethoxymethane and triethoxymethane.
Novel compounds of the following formula v and salts thereof: 
where R1, R2, R4 and R8 are as defined above may be formed as intermediates in the aforementioned method. In the presence of acid catalyst, the compound v or salt thereof undergoes conversion to a compound of the formula II or salt thereof.
For the conversion of a compound i to a compound I or II as described above, the present methods employ an xe2x80x9cacid catalystxe2x80x9d. Any acid catalyzing the method referred to may suitably be employed as the acid catalyst, with organic sulfonic acids (that is, organic acids containing the group SO2Oxe2x80x94) or sulfonates, or mineral acids being preferred. Particularly preferred such acid catalysts include pyridinium p-toluene sulfonate (PPTS), toluene sulfonic acid, camphor sulfonic acid, and the like.
The compounds of the formula i and salts thereof may exist as four stereoisomers with respect to the carbon atoms at those positions corresponding to the 4- and 5-position carbon atoms of the compounds of the formulae I and II. These stereoisomers are the following compounds of the formulae ia, ib, ic and id: 
A desired stereoisomer of a compound of the formula I or II or salt thereof may be prepared by the methods described above by employing the appropriate stereoisomer of the starting compound of the formula i or salt thereof. Thus, use of a compound ia can provide a compound Ia or IIa, use of a compound ib can provide a compound Id or IId, use of a compound ic can provide a compound Ic or IIc, and use of a compound id can provide a compound Ib or IIb. It is preferred to employ a single stereoisomer of the starting compound i or salt thereof in the above described methods, although stereoisomeric mixtures may also be employed. Use of a compound ia to prepare a compound Ia or IIa is particularly preferred.
Coupling to Prepare Oxazolidine Sidechain-bearing Taxanes
An oxazolidine sidechain-bearing taxane of the formula V or VIII or salt thereof may be prepared by a method comprising the step of contacting an oxazolidine compound of the formula III or VII, respectively, or salt thereof, in the presence of a coupling agent, with a taxane of the formula IV having a hydroxyl group directly bonded to C-13 thereof. The taxane starting material of the formula IV is preferably a compound such as those described in European Patent Publication No. 400,971, incorporated herein by reference, or a compound such as those described in U.S. patent application Ser. No. 08/995,443, filed Dec. 23, 1992 by Poss et al., or continuation-in-part thereof U.S. patent application Ser. No. 08/171,792, filed Dec. 22, 1993, both also incorporated herein by reference. Exemplary such taxanes include those of the following formula IX: 
where
R11 is hydrogen, hydroxyl, R15xe2x80x94Oxe2x80x94, R16xe2x80x94C(O)xe2x80x94Oxe2x80x94, or R16xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94;
R12 is hydrogen, hydroxyl, fluoro, R15xe2x80x94Oxe2x80x94, R16xe2x80x94C(O)xe2x80x94Oxe2x80x94 or R16xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94;
R13 and R14 are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclo;
R15 is a hydroxyl protecting group; and
R16 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl or heterocyclo,
or salts thereof.
All stereoconfigurations of the unspecified chiral centers of the compound of the formula IX are contemplated for use in the coupling method of the present invention. The use of a single stereoisomer is preferred, although mixtures thereof may be employed. 7-Trialkylsilyl baccatin III compounds are preferably employed as the compounds of the formula IV, most preferably, 7-trimethylsilyl baccatin III or 7-triethylsilyl baccatin III.
Any compound capable of effecting the coupling reaction may be employed as the coupling agent of the present invention. Exemplary coupling agents include one or more compounds forming an activated oxazolidine ester (for example, 1-hydroxybenzotriazole or N-hydroxysuccinimide, both of these with dicyclohexylcarbodiimide (DCC)) or anhydride (for example, an acid chloride such as pivaloyl chloride or bis(2-oxo-3-oxazolidinyl)-phosphinic chloride) when contacted with an oxazolidine of the formula III or VII, particularly coupling agents comprising a compound such as a carbodiimide (e.g., dicyclohexylcarbodiimide (DCC), 1,3-diisopropylcarbodiimide (DIC), or 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride), bis(2-oxo-3-oxazolidinyl)phosphinic chloride), carbonyl diimidazole (CDI), pivaloyl chloride, or 2,4,6-trichlorobenzoyl chloride; wherein the aforementioned compounds are preferably employed together with a compound such as 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HO-Su), or an amine such as triethylamine, pyridine or pyridine substituted at the 4-position with xe2x80x94N(R17) (R18), where R17 and R18 are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or heterocyclo (to form a compound such as 4-dimethylaminopyridine (DMAP)), or where R17 and R18, together with the nitrogen atom to which they are bonded, form a heterocyclo group (to form a compound such as 4-morpholinopyridine or 4-pyrrolidinopyridine).
Ring Opening to Form Taxanes of the Formula VI
A sidechain-bearing taxane of the formula VI or salt thereof may be prepared from an oxazolidine sidechain-bearing taxane of the formula V or VIII or salt thereof, by a method comprising the step of contacting said taxane of the formula V or VIII or salt thereof with a ring-opening agent capable of opening the ring of the oxazolidine group bonded through C-13 of the taxane noiety. of said taxane compound to form said taxane compound of the formula VI or salt thereof.
A preferred class of ring-opening agents for the conversion of a compound V or salt thereof to a compound VI or salt thereof are Lewis acids which preferably cause minimal or, most preferably, no decomposition of the compounds V or VI or salts thereof (xe2x80x9cmild Lewis acidsxe2x80x9d). Any Lewis acid capable of effecting the aforementioned ring opening may be employed in the method of the present invention. Exemplary such agents include palladium containing agents such as Pd(CH3CN)2Cl2.
A preferred class of ring-opening agents for the conversion of a compound VIII or salt thereof to a compound VI or salt thereof are protic acids. Any protic acid capable of effecting the aforementioned ring opening may be employed in the method of the present invention. Exemplary such ring-opening acids include organic carboxylic acids, such as acetic acid or trifluoroacetic acid, and/or mineral acids such as hydrochloric acid, hydrofluoric acid or sulfuric acid, in water.
The compounds of the formula VI and salts thereof may exist as four stereoisomers with respect to the carbon atoms at those positions corresponding to the 4- and 5-position carbon atoms of the compounds of the formulae I and II. These stereoisomers are the following compounds of the formulae VIa, VIb, VIc and VId: 
A desired stereoisomer of the compound of the formula VI or salt thereof may be prepared by the methods described above by employing the appropriate stereoisomer of the starting compound of the formula III or VII or salt thereof. Using the designations xe2x80x9caxe2x80x9d through xe2x80x9cdxe2x80x9d to refer to the stereoisomers of the formulae III and VII as are used for the compounds I and II above: use of a compound IIIa or VIIa will provide a compound VIa; use of a compound IIId or VIId will provide a compound VIb; use of a compound IIIc or VIIc will provide, predominantly, a compound VIa along with a minor amount of a compound VIc; and use of a compound IIIb or VIIb will provide, predominantly, a compound VIb along with a minor amount of a compound VId. It is preferred to employ a single stereoisomer of the starting compound III or VII or salt thereof in the above described methods, although stereoisomeric mixtures may also be employed. Use of a compound Ia to prepare a compound VIa is particularly preferred.
A preferred embodiment of the present invention further comprises the step of deprotecting one or more groups, particularly to free hydroxyl groups, on the taxane moiety to prepare taxanes of the formula VI or salts thereof. Deprotection may, for example, be conducted prior or subsequent to, or simultaneously with, the aforementioned ring opening methods by use of a deprotection agent. Any compound capable of deprotection may be employed as the deprotection agent. For example, acids such as hydrofluoric acid or aqueous protic acids, or tetra-alkylammonium fluorides such am tetra-n-butylammonium fluoride, may be employed for removal of silyl protecting groups; benzyl protecting groups may be removed by hydrogenation; trichloroethoxycarbonyl protecting groups may be removed by contact with zinc; and acetal or ketal protecting groups may be removed by the use of protic acids or Lewis acids.
A particularly preferred embodiment of the present invention comprises simultaneous ring opening and deprotection of one or more hydroxyl groups on the taxane ring structure, particularly at C-7, such as by the use of an acid (e.g., a mineral acid such as hydrochloric acid) capable of effecting both ring opening and deprotection simultaneously. Thus, for example, use of an acid agent under reaction conditions described above for ring opening may allow simultaneous ring opening and deprotection of cleavable hydroxyl protecting groups at C-7 such as trialkylsilyl (e.g. trimethylsilyl or triethylsilyl).
Preferred Reaction Conditions
The methods of the present invention may be conducted under any conditions, such as temperature, pressure and time, and using the appropriate starting materials and catalysts in any relative amount, effective to achieve the desired conversion. Similarly, a solvent may be employed if desired and may be selected from any material in which the conversion may be conducted, including inorganic (e.g., aqueous) or organic (e.g., acetone, dimethylformamide, tetrahydrofuran, methylene chloride, acetonitrile, benzene or toluene) liquids or mixtures thereof. Solvents are preferably employed which are inert to the reaction.
The products of the methods of the present invention may be isolated and purified by any suitable methodology such as extraction, distillation, crystallization, column chromatography, and the like.
Particularly preferred reaction conditions for conducting various methods described herein are set forth in the following Tables 1 to 6.
Salts or solvates such as hydrates of reactants or products may be employed or prepared as appropriate in any of the methods of the present invention. Unless otherwise indicated, reference to a compound herein is understood to include salts and/or solvents thereof.
Compound iv can be formed as an intermediate and converted to a compound of the formula I in situ due to the presence of acid catalyst, or contacted with acid catalyst in a separate step.
Compound v can be formed as an intermediate and converted to a compound of the formula II.
As described above, use of the base only can provide a formula III or VII salt; further use of an acid provides the free carboxylic acid.
Preferred Groups
Preferred groups forming part of compounds used or prepared by the present invention are those where:
R1 and R1* are each independently arylcarbonyl (especially benzoyl) or alkyloxycarbonyl (especially unsubstituted lower alkyloxycarbonyl such as tert-butoxycarbonyl);
R2 is phenyl, thienyl or furyl;
R3 is hydrogen or R3P where R5, R6 and R7 are each independently unsubstituted lower alkyl (especially, methyl or ethyl);
R4 is hydrogen or unsubstituted lower alkyl (especially, methyl or ethyl);
R5, R6 and R7 are each independently unsubstituted lower alkyl (especially, methyl or ethyl);
R8 is unsubstituted lower alkyl (especially methyl or ethyl); and
T is the moiety: 
where
R9 is hydrogen, alkylcarbonyl, or a hydroxyl protecting group, especially acetyl; and
R10 is hydrogen or a hydroxyl protecting group, especially a trialkylsilyl group such as triethylsilyl or trimethylsilyl.
C-13 Acyloxy Sidechain-bearing Taxanes
The addition of a C-13 acyloxy sidechain as described herein, in and of itself, may impart an increased or more desirable pharmacological activity to the taxane product, or may form a taxane product which is more readily converted to a taxane having an increased or more desirable pharmacological activity than the starting compound. Exemplary taxanes which may be prepared by the present methods for the preparation of sidechain-bearing taxanes include those taxanes described in European Patent Publication No. 400,971, and U.S. patent application Ser. No. 07/995,443, filed Dec. 23, 1992 and Ser. No. 08/171,792, filed Dec. 22, 1993, all incorporated herein by reference. It is preferred to ultimately prepare taxotere or, most preferably, paclitaxel according to the methods of the present invention.
Pharmacologically active taxanes such as paclitaxel may be used as antitumor agents to treat patients suffering from cancers such as breast, ovarian, colon or lung cancers, melanoma and leukemia.
As can be appreciated, the oxazolidines, taxanes and other compounds described herein may be present in more than one stereoisomeric form. All stereoisomers of the compounds described herein are contemplated, whether alone (that is, substantially free of other isomers), in admixture with certain stereoisomers (for example, as a racemate) or in any other mixture thereof. It is preferred that these compounds be substantially free of other stereoisomers.
The present invention is further described by the following examples which are illustrative only, and are in no way intended to limit the scope of the present claims.
The following abbreviations have the indicated meaning throughout the present specification.
Ac=acetyl
Bz=xe2x80x94C(O)-Ph (i.e., benzoyl)
DCC=dicyclohexylcarbodiimide
DMAP=dimethylaminopyridine
DMF=dimethylformamide
Et=ethyl
EtOAc=ethyl acetate
MOP=1-methoxy-1-methylethyl
Ph=phenyl
HI=homogeneity index
PMA=phosphomolybdic acid
PPTS=pyridinium p-toluene sulfonate
TEA=triethylamine
TES=triethylsilyl
THF=tetrahydrofuran
TLC=thin layer chromatography
The following Examples 1 to 4 demonstrate cyclizations forming a preferred oxazolidine ester compound of the formula I or II of the present invention.